Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.
Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.
复制标题
DOI：
--
复制
发表时间：
2013
影响因子：
2.5
通讯作者：
Changning Wang;T. Eessalu;V. Barth;C. Mitch;F. Wagner;Yijia Hong;R. Neelamegam;Frederick A. Schroeder;E. Holson;S. Haggarty;J. Hooker
中科院分区：
文献类型：
--
作者：
Changning Wang;T. Eessalu;V. Barth;C. Mitch;F. Wagner;Yijia Hong;R. Neelamegam;Frederick A. Schroeder;E. Holson;S. Haggarty;J. Hooker
羟肟酸基组蛋白去乙酰化酶抑制剂（hdac）是一类具有治疗潜力的分子，目前反映在使用亚羟肟酸胺（SAHA；伏立他）治疗皮肤t细胞淋巴瘤（CTCL）。HDAC抑制剂可能具有癌症治疗之外的用途，因为临床前研究已将HDAC抑制剂归因于心脏病、糖尿病、抑郁症、神经变性和其他中枢神经系统（CNS）疾病等领域的有益作用。然而，对羟酸盐的药代动力学（PK）知之甚少，特别是关于中枢神经系统的渗透、分布和保留。为了利用正电子发射断层扫描（PET）研究基于羟肟酸的HDAC抑制剂对啮齿动物和非人灵长类动物（NHP）脑的通透性，我们修改了belinostat （PXD101）和panobinostat （lhh -589）的结构以加入碳-11。我们还通过碳同位素取代标记了PCI 34051。在表征了这些化合物在9种重组HDAC亚型（跨越I类和II类家族成员）中的体外亲和力和功效后，我们确定了每种抑制剂的脑摄取。当静脉注射给啮齿动物和NHPs时，每种标记的化合物在脑组织中的吸收率都很低。在啮齿类动物研究中，我们观察到放射性示踪剂的脑积累不受预施用未标记抑制剂的影响。考虑到cns穿透可能对成像应用和治疗都是理想的，我们探索了液相色谱-串联质谱（LC-MS-MS）预测脑外显率的方法是否适合在PET放射标记之前预筛选化合物（羟肟酸基HDACi）。LC-MS-MS数据确实有助于识别额外的铅分子，以探索PET显像剂来可视化体内的HDAC酶。然而，LC-MS-MS预测的HDACi脑外显率与PET成像结果没有很强的相关性。这强调了体内PET成像工具在表征假定的中枢神经系统药物先导化合物方面的重要性，以及继续需要发现有效的PET示踪剂用于神经表观遗传成像。
Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.